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Abstract
We examined the role of phospholipase D2 (PLD2) on acetaminophen (APAP)-induced acute liver injury using a PLD2 inhibitor (CAY10594). 500 mg/kg of APAP challenge caused acute liver damage. CAY10594 administration markedly blocked the acute liver injury in a dose-dependent manner, showing almost complete inhibition with 8 mg/kg of CAY10594. During the pathological progress of acute liver injury, GSH levels are decreased, and this is significantly recovered upon the administration of CAY10594 at 6 hours post APAP challenge. GSK-3β (Serine 9)/JNK phosphorylation is mainly involved in APAP-induced liver injury. CAY10594 administration strongly blocked GSK-3β (Serine 9)/JNK phosphorylation in the APAP-induced acute liver injury model. Consistently, sustained JNK activation in the cytosol and mitochondria from hepatocytes were also decreased in CAY10594-treated mice. Many types of immune cells are also implicated in APAP-induced liver injury. However, neutrophil and monocyte populations were not different between vehicle- and CAY10594-administered mice which are challenged with APAP. Therapeutic administration of CAY10594 also significantly attenuated liver damage caused by the APAP challenge, eliciting an enhanced survival rate. Taken together, these results indicate that PLD2 is involved in the intrinsic response pathway of hepatocytes driving the pathogenesis of APAP-induced acute liver injury, and PLD2 may therefore represent an important therapeutic target for patients with drug-induced liver injury.
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1 Sungkyunkwan University, Department of Biological Sciences, Suwon, Republic of Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X); Institute for Stem Cell & Regenerative Medicine Research of Albert Einstein College of Medicine, Bronx, USA (GRID:grid.251993.5) (ISNI:0000000121791997)
2 Sungkyunkwan University, Department of Biological Sciences, Suwon, Republic of Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X)
3 Sungkyunkwan University, Department of Health Sciences and Technology, SAIHST, Seoul, Republic of Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X)
4 POSTECH, Department of Life Science, Pohang, Republic of Korea (GRID:grid.49100.3c) (ISNI:0000 0001 0742 4007)
5 Veterans Affairs Hospital, Palo Alto Veterans Institute for Research, Palo Alto, USA (GRID:grid.49100.3c)
6 Sungkyunkwan University, Department of Biological Sciences, Suwon, Republic of Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X); Sungkyunkwan University, Department of Health Sciences and Technology, SAIHST, Seoul, Republic of Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X)